Identifying genetic-risk factors associated with Alzheimers disease (AD) is critical to progress against the disease. Recently, several groups identified a region of chromosome-10 as containing at least one susceptibility locus for late-onset AD (1-3), with one group additionally associating this region with enhanced plasma levels of amyloid-Beta (AB) (1). The gene encoding urokinase-type plasminogen activator (uPA) maps within this implicated region. Previously, we reported that uPA is induced by AB-treated neurons in vitro and in the Hsiao mouse model of AB burden in vivo (4). Moreover, uPA converts plasminogen to the active protease plasmin, which degrades both non-aggregated and aggregated AB with physiologic efficiency (Preliminary Results and [4, 5]). AB accumulation is a hallmark of AD, and may be causal to this disease. Considering these data overall, we hypothesize that one of the chromosome-10 loci is an uPA polymorphism that modulates uPA's ability to contribute, to AB clearance. To assess this hypothesis, we propose to: 1) evaluate the frequency of uPA polymorphisms in AD and control patients to identify polymorphism(s) segregating with AD. In preliminary work, we have identified an uPA polymorphism that significantly segregates with AD susceptibility. This polymorphism causes a leu for pro-change at position 141 within uPA, and alters binding of the uPA zymogen to aggregated fibrin; 2) gain insight into the possible roles of leu-uPA versus pro-uPA by comparing individuals homozygous, for leu-uPA versus pro-uPA for relevant clinical and neuropathologic markers of AD, including uPA localization in AD brain; 3) evaluate the ability of leu- uPA versus pro-uPA to bind AB, activate plasminogen, and inhibit AB neurotoxicity in vitro; and 4) evaluate the role of uPA in AB clearance in vivo by quantifying AB accumulation in mice that are wild-type or genetically deficient for uPA. Overall, the focused approach proposed here will: 1) directly evaluate the possible role of uPA polymorphisms as a risk factor(s) for AD; and 2) provide insights into possible mechanisms underlying the differential uPA actions. These studies are significant, in that the identification of additional genetic risk factors for AD will aide in early AD diagnosis, and thereby facilitate drug discovery by identifying patients at high-risk for AD prior to symptomology. Moreover, by evaluating possible mechanisms underlying the enhanced susceptibility to AD, these studies may lead to the discovery of novel insights into the molecular mechanisms underlying AD, and thereby suggest new therapeutic approaches.